Department of Chemistry, Emory University, 1515 Dickey Drive, Atlanta, GA 30322, USA.
Chemistry. 2011 Dec 23;17(52):14792-804. doi: 10.1002/chem.201102630. Epub 2011 Nov 30.
A series of conformationally restrained epothilone analogues with a short bridge between the methyl groups at C6 and C8 was designed to mimic the binding pose assigned to our recently reported EpoA-microtubule binding model. A versatile synthetic route to these bridged epothilone analogues has been successfully devised and implemented. Biological evaluation of the compounds against A2780 human ovarian cancer and PC3 prostate cancer cell lines suggested that the introduction of a bridge between C6-C8 reduced potency by 25-1000 fold in comparison with natural epothilone D. Tubulin assembly measurements indicate these bridged epothilone analogues to be mildly active, but without significant microtubule stabilization capacity. Molecular mechanics and DFT energy evaluations suggest the mild activity of the bridged epo-analogues may be due to internal conformational strain.
设计了一系列具有 C6 和 C8 位甲基之间短桥的构象限制型埃坡霉素类似物，以模拟我们最近报道的 EpoA-微管结合模型所赋予的结合构象。已经成功设计并实施了一种用于这些桥连埃坡霉素类似物的多功能合成途径。对化合物对 A2780 人卵巢癌细胞和 PC3 前列腺癌细胞系的生物评估表明，与天然埃坡霉素 D 相比，在 C6-C8 之间引入桥连基可使活性降低 25-1000 倍。微管组装测量表明，这些桥连埃坡霉素类似物具有轻度活性，但没有明显的微管稳定能力。分子力学和 DFT 能量评估表明，桥连 epo 类似物的温和活性可能是由于内部构象应变所致。
